There are over a million cases of pleural effusion due to malignancies and pneumothorax each year in the United States. While all of these are not candidates for pleurodesis, the percentage that receive pleura sclerosing therapy is high. "Pleurodesis" is the fusion of the visceral and parietal pleura resulting from the therapeutic injection of a substance into the pleural cavity. The injected substance causes fibrosis between the visceral and parietal pleura and obliteration of the potential space between the two. Current treatment involves the introduction of a non-specific irritant into the pleural space. This treatment is painful and not always satisfactory.
The initial event in the production of a pleurodesis is an injury to the pleura. An acute exudative pleural effusion develops within 12 hours of the installation of essentially all of the agents that are presently used for pleurodesis including talc (9), tetracycline derivatives (10), quinacrine (11), mitoxantrone (12) and bleomycin (4). The pleural fluid that accumulates after the intrapleural injection of these agents is initially characterized by a relatively high protein, LDH and neutrophil count. However, injury to the pleura, as evidenced by the production of an acute exudative pleural effusion, is not sufficient to induce a pleurodesis because many agents when injected into the pleural cavity produce an acute exudative effusion but do not produce a pleurodesis (11).
The response by the pleura to an injury is a complex and poorly understood multifactorial process which can result either in the development of fibrosis with the obliteration of the pleural space or in restoration of the pleura to its normal state. The histological patterns of pleural fibrosis associated with the administration of nitoxantrone (12), talc (9, 13) or tetracycline derivatives (14, 15) are different. The mechanisms by which pleurodesis follows the intrapleural administration of tetracycline derivatives and talc also appear to be different. The pleurodesis that follows talc can be blocked if corticosteroids are administered systemically (16) or by the administration of tumor necrosis factor alpha blocking antibodies (17). In contrast, the pleurodesis that follows doxycycline is not blocked by either of these agents (18).
The agents most commonly used for the production of a pleurodesis are the tetracycline derivatives, talc in a slurry, and bleomycin (1). None of these compounds is ideal. The injection of a tetracycline compound is at times very painful (2). The injection of talc leads to the development of the acute respiratory distress syndrome in a small percentage of recipients, and this syndrome is at times fatal (3). The injection of bleomycin does not induce pleurodesis in animals with a normal pleura (4) and the bleomycin itself is very expensive, costing more than $1000 per injection. As talc and other commonly used agents produce pleurodesis by inducing injury to the pleura which leads to inflammation and fibrosis (32), pain and fever are common side effects (29).
Because injecting talc to create a pleurodesis is associated with mortality, because injecting tetracycline derivatives is painful, and because injecting bleomycin is very expensive and relatively ineffective, there exists a great need to find a safe, well-tolerated and inexpensive method for creating a pleurodesis.
The present invention meets this need and overcomes the previous limitations and shortcomings in the art by providing a safe, well-tolerated, inexpensive effective method for creating a pleurodesis by using TGF.beta.2. Transforming growth factor beta-2, TGF.beta.2, a specific fibrogenic agent, is effective at causing pleurodesis. TGF.beta..sub.2 produces excellent pleurodesis in rabbit and sheep models of pleurodesis with less pleural inflammation than currently used agents (28). The pleura of sheep closely resembles the human pleura. Like humans, sheep have a thick pleura which receives its blood supply from the systemic circulation (28). Hence sheep are an accepted model for the study of pleural fluid dynamics (29, 30).